Cancers in the form of malignant tumors are the second leading cause of death in the United States after heart disease (U.S. Dept. of Health and Human Services, National Vital Statistics Reports, 58(19), May 20, 2010). Many cancers are characterized by an increase in the number of neoplastic cells originating from an initially normal tissue which subsequently propagate to form a tumor mass. With malignant tumors, neoplastic cells invade neighboring tissues ultimately leading to their spread via the blood or lymphatic system to lymph nodes and other locations distant from the site of the original tumor via a process called metastasis. Cancer manifests itself in a wide variety of forms, with each form characterized by varied degrees of invasiveness and aggressiveness.
Apoptosis is the regulated process of programmed cell death (PCD) which occurs in multicellular organisms. In response to certain external or internal cellular signaling events, cells undergo apoptosis which eventually leads to characteristic changes in cell morphology and cellular death. Normally, apoptosis is necessary for the function and development of multicellular organisms. In some cases, however, loss of apoptotic control can lead to a variety of diseases and conditions, including cancer. Over the past several years, many molecular pathways which modulate a cell's ability to control apoptotic processes have been identified. One such pathway is the Fas/Fas Ligand system.
Fas Ligand (a.k.a. FasL or CD95L) is a type-II transmembrane protein member of the tumor necrosis factor (TNF) superfamily. Binding of FasL to its receptor, known as Fas (a.k.a. CD95, Apo-1, and tumor necrosis factor receptor superfamily, member 6 (TNFRSf6)), induces apoptosis in those cells expressing Fas on their plasma membranes. Over the past two decades, the Fas/FasL system has been used to try to understand the role of apoptosis in cancers as well as to attempt to use components of the system to treat a number of proliferative diseases (See, e.g., Takahashi et al, International Immunology, 6(10):1567-74 (1994); Nagata et al., Science, 267:1449-1456 (1995); Takahashi et al., Cell, 66:969-976 (1994); Lee et al., FASEB J., 8(5):A770 (1994); Suda et al., Cell, 75:1169-78 (1993); Suda et al., Journal of Experimental Medicine, 179:873-879 (1994)). U.S. Patent Application Publication No. 2004/0224389 describes constructs encoding FasL and other apoptosis-inducing proteins, which were capable of inducing apoptosis in a desired target cell.
In some cases, biomarkers are gene expression products measured in blood or within a particular cell type whose concentration, existence, or lack thereof reflects the severity or presence of some disease state. In attempts to discover effective biomarkers for cancer diagnosis and therapy, researchers have sought to identify targets that are differentially expressed in cancer cells as compared to expression in or on one or more types of normal non-malignant cells. In some cases, identification of such tumor-associated biomarkers has given rise to the ability to specifically target cancer cells for destruction based on the differential relative expression of one or more particular biomarkers either within a cancer cell or expressed on its surface. However, complicating this strategy is the fact that, even within tumors originating from the same tissue type, substantial variation in gene expression patterns may exist between individuals or between subpopulations of individuals suffering from the same type of cancer. The advent of genome-wide gene expression profiling has permitted the molecular characterization of intertumoral gene expression variability, revealing molecular signatures that reflect underlying pathogenic mechanisms and molecular features that may be associated with survival in individual subtypes of tumors (Alizedeh et al, Nature, 403:503-511 (2000)). Identification of tumor subtypes is critical, as anti-cancer therapies that may be effective for the treatment of one subtype may not be similarly effective in treating other subtypes due to the consequences of variation in gene expression patterns.
Consequently, given the unreliability of individual gene expression within tumors of the same cancer type, there exists a need for a biomarker whose measurement can not only predict the likelihood that an individual with a particular tumor subtype will benefit from anti-cancer therapies, but whose expression is also useful for selecting individuals or subpopulations of individuals for a particular anti-cancer therapy. Such a diagnostic marker would be helpful for guiding health care professionals involved in the treatment of an individual suffering from particular subtypes of malignant tumors originating from the same tissue. A diagnostic marker of this sort would also be useful to track prognosis following the initiation of treatment.
This invention provides such a biomarker and uses the expression level of Fas within a tumor to select individuals or subpopulations of individuals who will benefit from an anti-cancer therapy.
Throughout this specification, various patents, patent applications and other types of publications (e.g., journal articles) are referenced. The disclosure of all patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety for all purposes.